P1027: UPDATED DURABILITY OF RESPONSE AND SAFETY IN MANIFEST ARM 3: PELABRESIB (CPI-0610) COMBINED WITH RUXOLITINIB FOR JAK INHIBITOR TREATMENT-NAÏVE PATIENTS WITH MYELOFIBROSIS
Authors: Claire Harrison, Andrea Patriarca, Vikas Gupta, Francesca Palandri, Timothy Devos, Raajit K Rampal, Moshe Talpaz, Alessandro Vannucchi, Andrew Kuykendall, Jean-Jacques Kiladjian, Srdan Verstovsek, Ruben Mesa, Gozde Colak, Soumik Dutta, Sandra Klein, Jie Cui, Tzuu-Wang Chang, John Mascarenhas
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: Myelofibrosis (MF) is characterized by progressive bone marrow (BM) fibrosis, splenomegaly and cytopenias resulting from aberrant megakaryopoiesis and proinflammatory cytokine expression. These processes are regulated by BET protein-mediated gene expression and lead to myeloproliferation and cytopenias. The current standard of care for patients with MF is treatment with the Janus kinase inhibitor (JAKi) ruxolitinib (RUX). However, unmet need persists with JAKi monotherapy due to limited depth and durability of responses, high rates of discontinuation and toxicities. Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other genes involved in MF disease pathways. PELA is under investigation as monotherapy and in combination with RUX in pts with MF in the ongoing Phase 2 MANIFEST study (NCT02158858). Aims: To report updated efficacy, safety, and biomarker results from Arm 3 (PELA + RUX in JAKi-naïve pts with MF) of the MANIFEST study. Methods: Pts received oral PELA 125 mg QD in 21-day cycles with continuous oral RUX at initial doses of 10 or 15 mg BID. The primary endpointis ≥35% spleen volume reduction from baseline (BL; SVR35) to 24 wks measured by imaging. The key secondary endpoint is ≥50% reduction in total symptom score (TSS50) at 24 wks. Results: At data cutoff (29 July 2022), 84 pts received ≥1 dose of PELA and RUX. Mean (SD) age was 67 (10) years; 23%, 62% and 16% pts had DIPSS Int-1, Int-2 or high risk, respectively. SVR35 was 68% (57/84) at Wk 24, 61% (51/84) at Wk 48 and 54% (45/84) at Wk 60. SVR35 at any time was observed in 80% (67/84) of evaluable pts; 70% (47/67) of pts with SVR35 maintained response at data cutoff. Median spleen volume change was –50% (range –84.4% to 27.9%) at Wk 24. Median time to SVR35 was 12 wks (range 10 to 51) with durable spleen volume reductions over time (Figure). TSS50 for evaluable pts was 56% (46/82) at Wk 24, 44% (36/82) at Wk 48 and 43% (35/82) at Wk 60. TSS50 at any time was achieved by 83% (68/82) of pts. Median change in TSS was −59% (range −100% to 225%) at Wk 24 with sustained symptom burden reduction over time. A mean Hb increase of ≥1.5 g/dL from BL without transfusions over 12 wks was observed in 30% (25/84) of pts. BM fibrosis improved by ≥1 grade in 27% (17/63) of pts at Wk 24; 59% (10/17) maintained BM improvement at >Wk 48 and 40% (25/63) had ≥1 grade improvement at any time. No pts had complete resolution of fibrosis (to Grade 0). A total of 59% (16/27) of pts had ≥15% increase in distance between nuclei of CD61+ cells in BM, and 38% (18/47) had ≥20% reduction in JAK2V617F variant allele fraction (VAF). An association of BM fibrosis and JAK2V617F VAF reductions was observed with SVR35 (8 pts), TSS50 (5 pts) and Hb responses (5 pts). The most common hematologic TEAEs were thrombocytopenia (55%; Gr ≥3: 17% pts; resulting in discontinuation in 5 pts [6%]) and anemia (43%; Gr ≥3: 35% pts). Serious AEs included anemia, pyrexia, COVID-19 (3 pts each), gastrointestinal hemorrhage, multiple organ dysfunction syndrome, pneumonia, urinary tract infection, respiratory tract infection, fall and respiratory failure (2 pts each). TEAEs leading to PELA discontinuation occurred in 12 pts (14%). Gr 5 TEAEs (7 pts) were assessed as unrelated to PELA, except multiple organ failure due to sepsis secondary to pneumonia. Conclusion: The combination of PELA and RUX in JAKi-naïve pts with MF showed clinically meaningful durable improvements in spleen volume and TSS, with improvement at 24 wks in Hb. Biomarker findings of potential disease-modifying activity included improvements in BM fibrosis and reductions in JAK2V617F VAF. Safety was consistent with previous reports.Keywords: Myelofibrosis, Inhibitor, Myeloproliferative disorder